The β-lactams remain the most widely used antibiotics and are consequently amongst the most important medicines in current use. β-Lactam antibiotics inhibit transpeptidases (penicillin binding proteins, PBPs) involved in cell wall biosynthesis by reacting with a nucleophilic serine-residue important in catalysis. The use of β-lactams is compromised by resistance mechanisms, including by the action of β-lactamases (BLs), which catalyse β-lactam hydrolysis. Four classes of BLs have been identified on the basis of substrate selectivity and structure. Classes A, C and D are ‘serine’ BLs and are evolutionarily and mechanistically related to the PBPs. Class B BLs are zinc dependent hydrolases that are mechanistically distinct.
Inhibitors of the Class A enzymes (‘penicillinases’), i.e. clavulanic acid, tazobactam, and sulbactam, have been developed and have substantially extended the spectrum of activity of otherwise Class A BL susceptible partner penicillins. Inhibitors of the Class C BLs (‘cephalosporinases’) are also being developed with one, Avibactam (NXL-104), being in late stage clinical trials. Moreover, Avibactam also targets Class A and some Class D enzymes, but not Class B MBLs. As yet, however, there are no reports of clinically useful inhibitors of the Class B metallo-BLs (MBLs).
MBLs are an increasing clinical concern since they catalyse the hydrolysis of almost all β-lactam antibiotics. Based on the number of Zn ions in their active site and sequence/structural similarities, MBLs can be subdivided into three subclasses (B1, B2 and B3). MBLs belonging to the B1 subclass are presently considered to be the most clinically relevant (e.g. IMP—Imipenemase, VIM—Verona integron-encoded MBL, and NDM—New Delhi MBL types) since they inactivate almost all BLs, including the latest generations of cephalosporins and all carbapenems, which are often considered “last resort antibiotics”. The potential threat of MBLs is highlighted by NDM-1, which enables resistance in many pathogenic strains. Further, an increasing number of organisms containing both serine BLs (SBLs) and MBLs are being reported. There is thus a need to develop not only MBL inhibitors, but compounds with dual SBL and MBL inhibition properties for use in combination therapies.